Our laboratory has focused on factors that influence host responses to tumors and may adversly influence responses to immunotherapy. The expression of tumor associated antigens by autologous human primary and metastatic sarcomas has been clearly defined using a panel of monoclonal antibodies. It has been demonstrated that primary tumors and their metastases express similar antigens but almost invariably, micro-heterogeneity of tumor antigen expression results from antigen absent populations of cells within each tumor. The mechanism of heterogeneity for tumor antigen expression of the B16 melanoma system has been defined using a tumor specific monoclonal antibody. Variation in antigen expression correlated with variations of tumor cell density in culture. Monoclonal antibodies have been produced that recognize antigens newly expressed by NIH 3T3 fibroblasts transfected with oncogenes from human tumors. These experiments define a new technique for the production of anti-tumor monoclonal antibodies and will also be useful in defining the mechanism of oncogene-related transformation. We have identified and immunoregulatory factor produced by a variety of human tumors that inhibits in vitro cell mediated immune responses. A murine melanoma that produces an immunosuppressive glycoprotein has also been identified and the glycoprotein has been characterized and purified. The in vivo immunosuppressive effects of murine melanoma derived glycoprotein have been demonstrated. A factor has been isolated from a variety of human tumors that inhibits thymidine incorporation by proliferating tumor cells and also inhibits tumor cell growth. The factor has been purified to homogeneity and the mechanism of its action has been determined. We are currently evaluating interactions between various modalities of immunotherapy to develop new techniques for the treatment of metastatic tumors.